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Background <p>Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs).</p> Objectives <p>This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs.</p> Methods <p>This phase I, non-randomised, open-label, two-period, fixed-sequence trial was conducted in healthy pre-menopausal female volunteers aged 18–35 years. In period 1, participants received a combined OC (ethinylestradiol 30 µg/levonorgestrel 150 µg once daily; reference treatment). In period 2, participants received a combined OC and iclepertin 10 mg once daily (test treatment). Primary pharmacokinetic endpoints of ethinylestradiol or levonorgestrel in plasma at steady state over a uniform dosing interval τ were area under the concentration–time curve (AUC<sub><i>τ</i>,ss</sub>) and maximum and minimum measured concentration (<i>C</i><sub>max,ss</sub> and <i>C</i><sub>min,ss</sub>); drug interaction potential was estimated by geometric mean ratios (test treatment/reference treatment) with two-sided 90% confidence intervals (CIs) using analysis of variance. Safety assessments included monitoring adverse events (AEs).</p> Results <p>In total, 19 participants entered the trial; 17 were treated (periods 1 and 2). Steady-state pharmacokinetics of ethinylestradiol and levonorgestrel were similar with and without iclepertin; geometric mean ratios for AUC<sub><i>τ</i>,ss</sub>, <i>C</i><sub>max,ss</sub>, and <i>C</i><sub>min,ss</sub> were slightly above 100%, and 90% CIs were within standard bioequivalence boundaries (80–125%). The number of on-treatment AEs was similar in period 1 (<i>n</i>&#xa0;=&#xa0;13) and period 2 (<i>n</i>&#xa0;=&#xa0;15); AEs were of mild-to-moderate severity.</p> Conclusion <p>Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly.</p> Trial Registration <p>ClinicalTrials.gov (NCT05613777; registered on 18 October 2023).</p>

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The Effect of Multiple Oral Doses of a Glycine Transporter 1 Inhibitor, Iclepertin (BI 425809), on the Steady-state Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel: a Phase I Clinical Trial in Healthy Females

  • 期刊论文

  • 发表日期：

    2025年9月4日

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  • Shilpa Madari,
  • Yesilda Balavarca,
  • Yury Shatillo,
  • Corey Reuteman-Fowler,
  • Michael Desch

摘要

Background

Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs).

Objectives

This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs.

Methods

This phase I, non-randomised, open-label, two-period, fixed-sequence trial was conducted in healthy pre-menopausal female volunteers aged 18–35 years. In period 1, participants received a combined OC (ethinylestradiol 30 µg/levonorgestrel 150 µg once daily; reference treatment). In period 2, participants received a combined OC and iclepertin 10 mg once daily (test treatment). Primary pharmacokinetic endpoints of ethinylestradiol or levonorgestrel in plasma at steady state over a uniform dosing interval τ were area under the concentration–time curve (AUCτ,ss) and maximum and minimum measured concentration (Cmax,ss and Cmin,ss); drug interaction potential was estimated by geometric mean ratios (test treatment/reference treatment) with two-sided 90% confidence intervals (CIs) using analysis of variance. Safety assessments included monitoring adverse events (AEs).

Results

In total, 19 participants entered the trial; 17 were treated (periods 1 and 2). Steady-state pharmacokinetics of ethinylestradiol and levonorgestrel were similar with and without iclepertin; geometric mean ratios for AUCτ,ss, Cmax,ss, and Cmin,ss were slightly above 100%, and 90% CIs were within standard bioequivalence boundaries (80–125%). The number of on-treatment AEs was similar in period 1 (n = 13) and period 2 (n = 15); AEs were of mild-to-moderate severity.

Conclusion

Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly.

Trial Registration

ClinicalTrials.gov (NCT05613777; registered on 18 October 2023).